DESCRIPTION: Hereditary hearing impairment accounts for >50% of severe childhood deafness. It can be associated with other inherited clinical features to form a recognized phenotype or occur in isolation. The latter type is more common and is referred to as non-syndromic hearing loss. Usually inherited in a recessive fashion (autosomal recessive non-syndromic hearing loss, ARNSHL), epidemiological studies strongly implicate monogenic, though heterogeneous, disease loci, the number of which may exceed 100. Paradoxically although the number of genes is numerous, recessive inheritance has severely hampered localization efforts. Large single families suitable for linkage analysis are not common and pooling multiple small families is not feasible. Only seven genes responsible for ARNSHL have been reported, and none has been cloned. Endogamous populations were used in three instances, and small consanguineous families, in four. The specific aims of this grant are to localize ARNSHL genes by homozygosity mapping in multiplex consanguineous families, to identify candidate ARNSHL genes by direct cDNA selection, to demonstrate mutations in candidate genes, and to offer genetic counseling to families. By localizing many of the relevant ARNSHL genes and cloning the more common ones, this research will lead to a better understanding of hereditary hearing impairment in the United States. Appropriate mouse mutants will be identified, permitting studies in development, gene-gene interactions, and ultimately, therapeutic intervention.